ATTEMPTS: a heparin/protamine-based delivery system for enzyme drugs
ATTEMPTS: a heparin/protamine-based delivery system for enzyme drugs
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DOI：
10.1016/s0168-3659(01)00484-9
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发表时间：
2002-01-17
影响因子：
10.8
通讯作者：
Yang, VC
中科院分区：
文献类型：
--
作者：
Liang, JF;Li, YT;Yang, VC
一种被称为“抗体靶向、触发、电修饰前药类型策略（ATTEMPTS）”的前药递送系统已被开发出来，以允许抗体定向施用包括组织型纤溶酶原激活剂（tPA）在内的非活性酶药物，并允许随后在目标位点触发释放活性tPA。阳离子修饰的 tPA (rntPA) 通过离子相互作用附着在肝素-抗纤维蛋白复合物上，随后可以通过添加竞争性肝素抑制剂鱼精蛋白来释放活性 tPA。抗纤维蛋白 IgG 通过端点连接与肝素缀合，形成肝素-抗纤维蛋白复合物，提供最终肝素/mtPA 复合物的靶向效率。阳离子修饰通过用N-琥珀酰亚胺-3-(2-吡啶基二硫代)丙酸酯将(Arg)(7)Cys连接至tPA进行化学缀合或通过重组DNA方法进行。结果表明，在纤溶酶原激活、纤维蛋白结合能力和对纤维蛋白原的反应方面，tPA 的比活性没有显着改变。由于附着的肝素堵塞了 tPA 的活性位点，两种修饰的 tPA-肝素复合物均未产生任何内在催化活性。另一方面，肝素诱导的修饰 tPA 活性的抑制可通过添加鱼精蛋白来逆转，这与前药递送系统类似。这些结果表明，基于肝素/鱼精蛋白的酶递送系统可能是通过调节活性酶的释放和中止相关的全身毒性作用来改善当前酶治疗状态以及溶栓治疗的有用工具。目前，酶药物的修饰已通过计算机模拟辅助的重组DNA技术进行优化。此外，对原来的策略进行了修改，以获得增强的治疗效果。 (C) 2002 Elsevier Science B.V. 保留所有权利。
A prodrug delivery system termed "Antibody Targeted, Triggered, Electrically Modified Prodrug-Type Strategy (ATTEMPTS)" has been developed to permit the antibody-directed administration of inactive enzyme drug including tissue-type plasminogen activator (tPA), and allow a subsequent triggered release of the active tPA at the target site. Cation-modified tPA (rntPA) was attached to a heparin-antifibrin complex via ionic interaction, and the active tPA can subsequently be released by the addition of protamine, a competitive heparin inhibitor. Anti-fibrin IgG was conjugated to heparin via an end-point attachment to form the heparin-antifibrin complex which provides the targeting efficiency of the final heparin/mtPA complex. Cation modification was performed by either chemical conjugation by linking (Arg)(7)Cys to tPA with N-succinimidy-3-(2-pyridyldithio) propionate or by recombinant DNA methods. Results show that the modification process did not significantly after the specific activity of tPA with regard to plasminogen activation, fibrin-binding ability, and response toward fibrinogen. The complexes of both modified tPA-heparin did not yield any intrinsic catalytic activity owing to the blockage of the active site of tPA by the attached heparin. On the other hand, heparin-induced inhibition of modified tPA activity was reversed by adding protamine, which is similar to that of a prodrug delivery system. These results suggest that heparin/protamine-based enzyme delivery systems may be a useful tool to improve current enzyme therapeutic status, as well as thrombolytic therapy, by both regulating the release of active enzyme and aborting the associated systemic toxic effect. Currently, modification of enzyme drugs has been optimized by recombinant DNA technology assisted by computer simulation. In addition, the original strategy has been revised to obtain enhanced therapeutic efficacy. (C) 2002 Elsevier Science B.V. All rights reserved.